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Nair N, Du D, Johnston H, Mahesh B. Risk Prediction of Post-Transplant Lymphoproliferative Disease in Heart Transplant Patients. ASAIO J 2025:00002480-990000000-00679. [PMID: 40197378 DOI: 10.1097/mat.0000000000002433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025] Open
Abstract
Post-transplant lymphoproliferative disease (PTLD) represents the second most frequent malignancy in cardiac allograft recipients and constitutes up to 10% of de novo cancers. This study attempts to determine risk factors in adult heart transplant patients to develop a risk prediction model using the Scientific Registry of Transplant Recipients database and the lasso regression model. Data on 55,150 adult heart transplant patients (1987-2021) were extracted. The χ 2 /Wilcoxon tests were performed to identify significant variables ( p < 0.05). The dataset was divided into two. One set was used for model development/validation, and the other for simulating external validation. Lasso logistic regression models were developed to predict disease at 1, 3, and 5 years post-transplant. Cyclosporine, positive donor Epstein-Barr Virus (EBV) IgG, induction with OKT3, and the donor's human leukocyte antigen (HLA) B38 antigen had a higher risk at 3 and 5 years post-transplant. African American recipients have a lower risk of developing PTLD as compared with other ethnic groups. This is the first report of a lasso regression model with good discriminatory power ( c statistic of >0.7) in testing and validation cohorts. Future studies need to explore advanced modeling technologies and artificial intelligence systems capable of capturing patient diversity.
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Affiliation(s)
- Nandini Nair
- From the Division of Cardiology, Department of Medicine, Heart and Vascular Institute, Penn State Health/PSUCOM, Hershey, Pennsylvania
| | - Dongping Du
- Department of Industrial, Manufacturing and Systems Engineering, Texas Tech University, Lubbock, Texas
| | - Henry Johnston
- Department of Industrial, Manufacturing and Systems Engineering, Texas Tech University, Lubbock, Texas
| | - Balakrishnan Mahesh
- Division of Cardiothoracic Surgery, Department of Surgery, Heart and Vascular Institute, Penn State Health/PSUCOM, Hershey, Pennsylvania
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2
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Unal S. Comment on: Testosterone deficiency in men with end stage renal disease and kidney transplantation: a narrative review. Int J Impot Res 2025; 37:338-339. [PMID: 39833566 DOI: 10.1038/s41443-025-01014-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/06/2025] [Accepted: 01/09/2025] [Indexed: 01/22/2025]
Affiliation(s)
- Selman Unal
- Department of Urology, Urgup State Hospital, Nevsehir, Turkey.
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3
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Campillo P, Kesler A, Ramírez CA, Ramírez CJ, Daher JC, Grimm M, Sabina M, Bizanti A. International incidence of melanoma in heart transplant recipients: a meta-analysis. Melanoma Res 2025; 35:24-30. [PMID: 39365850 PMCID: PMC11670907 DOI: 10.1097/cmr.0000000000001008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/17/2024] [Indexed: 10/06/2024]
Abstract
The incidence of heart transplants in the USA has increased by 85.8% since 2011, resulting in a growing population of recipients requiring long-term immunosuppressive therapy. While essential for preventing organ rejection, this therapy significantly increases melanoma risk. This meta-analysis investigates the incidence and risk factors of melanoma in heart transplant recipients. A systematic review and meta-analysis were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, including observational studies reporting melanoma incidence in heart transplant recipients. Relative risk (RR) was synthesized from standardized incidence ratios, hazard ratios, incidence rate ratios, and standardized mortality ratios. The meta-analysis incorporated 10 studies, including 22 415 heart transplant recipients. The pooled RR was 2.21 (95% confidence interval: 1.32-3.71; P = 0.003), indicating a significantly elevated melanoma risk. This study highlights the critical need for preventive dermatological strategies in heart transplant recipients and calls for further research into the impact of different immunosuppressive regimens on melanoma risk. Despite limitations, these findings offer valuable insights for optimizing long-term patient care.
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Affiliation(s)
- Paola Campillo
- Department of Internal Medicine, Lakeland Regional Health Medical Center, Lakeland, Florida, USA
| | - Alice Kesler
- Department of Internal Medicine, Lakeland Regional Health Medical Center, Lakeland, Florida, USA
| | - Camila A. Ramírez
- Department of Internal Medicine, Lakeland Regional Health Medical Center, Lakeland, Florida, USA
| | - Carlos J. Ramírez
- Department of Internal Medicine, Lakeland Regional Health Medical Center, Lakeland, Florida, USA
| | - Jean Carlo Daher
- Department of Internal Medicine, Lakeland Regional Health Medical Center, Lakeland, Florida, USA
| | - Mason Grimm
- Department of Internal Medicine, Lakeland Regional Health Medical Center, Lakeland, Florida, USA
| | - Michael Sabina
- Department of Internal Medicine, Lakeland Regional Health Medical Center, Lakeland, Florida, USA
| | - Anas Bizanti
- Department of Internal Medicine, Lakeland Regional Health Medical Center, Lakeland, Florida, USA
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Erard D, Steiner A, Boillot O, Thimonier E, Vallin M, Veyre F, Guillaud O, Radenne S, Dumortier J. Calcineurin-Inhibitor Discontinuation Could Reduce the Risk of De Novo Malignancies After Liver Transplantation for Alcohol-Related Liver Disease. Clin Transplant 2024; 38:e70014. [PMID: 39552184 DOI: 10.1111/ctr.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 05/29/2024] [Accepted: 10/14/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND De novo malignancies are one of the leading causes of death after liver transplantation (LT), particularly in patients transplanted for alcohol-related liver disease (ALD). This retrospective study aimed to assess risk factors for malignancies and to evaluate the impact of calcineurin inhibitor (CNI) discontinuation. METHODS From 1990 to 2015, all patients transplanted for ALD were included. RESULTS A total of 493 patients were included, 77.9% were male and the median age at LT was 54 years. After LT, 278 de novo malignancies were diagnosed in 214 patients (43.4%). The cumulative incidence of de novo malignancies was 16.3% at 5 years, 34.4% at 10 years, and 49.8% at 15 years. In multivariate analysis, the independent risk factors were male gender (HR = 1.6), and active or weaned smoking (HR = 2.0). Discontinuation of CNI was a protective factor (HR = 0.6). Survival after diagnosis of de novo malignancy was 42.7% at 5 years and 27.5% at 10 years. CONCLUSION Our results confirm the major incidence of de novo malignancies after LT for ALD, as well as the important role of non-modifiable risk factors such as smoking and gender. CNI discontinuation is a protective factor, and the only adaptable, and could be proposed in smoker male patients transplanted for ALD.
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Affiliation(s)
- Domitille Erard
- Service d'hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
| | - Anouk Steiner
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Olivier Boillot
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
- Université Claude Bernard Lyon 1, Lyon, France
| | - Elsa Thimonier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Mélanie Vallin
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Florian Veyre
- Service d'hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
| | - Olivier Guillaud
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Sylvie Radenne
- Service d'hépatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
| | - Jérôme Dumortier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
- Université Claude Bernard Lyon 1, Lyon, France
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Freitas GRR, Fernandes MDL, Agena F, Lemos FBC, de Paula FJ, Coelho V, David-Neto E, Galante NZ. Effects of two immunosuppression regimens on T-lymphocyte subsets in elderly kidney transplant recipients. Front Immunol 2024; 15:1405855. [PMID: 39372414 PMCID: PMC11449757 DOI: 10.3389/fimmu.2024.1405855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 08/06/2024] [Indexed: 10/08/2024] Open
Abstract
Background Despite the growing number of elderly kidney transplant (Ktx) recipients, few studies have examined the effects of immunosuppression on their lymphocyte profiles. Methods We evaluated the early conversion from mycophenolate sodium (MPS) to everolimus (EVL) after rabbit antithymocyte globulin (rATG) 2 mg/kg induction in elderly kidney recipients. Three groups of KTx patients were compared: (a) Young (n=20, 36 ± 7 y) receiving standard immunosuppression (Group A1) (prednisone, tacrolimus, and MPS), (b) Elderly (n=35, 65 ± 3 y) receiving standard immunosuppression (Group B1), and (c) Elderly (n=16, 65 ± 3 y) with early (mean 30 d) conversion from MPS to EVL (Group B2). Naive, memory, and regulatory peripheral blood TCD4+ lymphocytes were quantified at 0, 30, and 365 d. Results Results are reported as [mean(p25-p75)]. Young recipients had higher lymphocyte counts at baseline [2,100(1,630-2,400) vs. 1,310 (1,000-1,600)/mm3, p<0.0001] maintained higher counts within 365 d [1,850(1,590-2,120) vs. 1,130(460-1,325)/mm3, p=0.018 and vs. 1,410(805-1,895)/mm3, p=0.268]. Elderly recipients showed a decrease in lymphocytes within 30 d [1,310(1,000-1,600) vs. 910(700-1,198)/mm3, p=0.0012] with recovery within 365 d. The same pattern was observed in total lymphocytes and TCD4+ counts. Rabbit antithymocyte globulin induced a reduction in central memory T-cell percentages at 30 d in both young recipients [6.2(3.77-10.8) vs. 5.32(2.49-7.28)% of CD4+, p=0.036] and in elderly recipients [8.17(5.28-12.88) vs. 6.74(4.36-11)% of CD4+, p=0.05] on standard immunosuppression, returning to baseline at 365 d in elderly recipients but not in young recipients. Regulatory T CD39+ cells (Treg) percentages decreased at 30 d in elderly recipients [2.1(1.23-3.51) vs. 1.69(0.8-2.66)% of CD4+, p=0.0028] and in young recipients [1.29(0.45-1.85) vs. 0.84(0.18-1.82)% of CD4+, p=0.0038], returning to baseline at 365 d in elderly recipients [2.1(1.23-3.51) vs. 2.042(0.88-2.42)% of CD4+], but not in young recipients [1.29(0.45-1.85) vs. 0.86(0.7-1.34) % of CD4+]. The elderly everolimus conversion group did not show significant changes in cell profile over time or compared to elderly recipients with standard immunosuppression. Conclusion Aging favored the maintenance of Treg during the late transplantation period despite ongoing immunosuppression. Lymphocyte depletion due to rATG was more prominent in elderly recipients and affected memory subsets with a temporary reduction in central memory T cells. However, conversion to everolimus did not impact Treg profile. Reducing the dose of rATG in elderly recipients seems necessary for the expected lymphocyte changes with EVL to occur. Clinical trial registration nEverOld Trial, identifier NTC01631058.
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Affiliation(s)
- Geraldo Rubens R. Freitas
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Departamento de transplante renal, Hospital Universitário de Brasília (HUB), Empresa Brasileira de Serviços Hospitalares (EBSERH), Brasília, Brazil
| | - Maria da Luz Fernandes
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Fabiana Agena
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Francine B. C. Lemos
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Flavio J. de Paula
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Verônica Coelho
- Laboratório de Imunologia, Instituto do Coração, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Laboratório de Investigação Médica 19 (LIM-19), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Instituto de Investigação em Imunologia, Instituto Nacional de Ciência e Tecnologia (iii-INCT), São Paulo, Brazil
| | - Elias David-Neto
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Nelson Z. Galante
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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Szeimies RM, Ulrich C, Ferrándiz-Pulido C, Hofbauer GFL, Lear JT, Lebbé C, Piaserico S, Hædersdal M. The "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) Project: An Expert Panel Opinion. Dermatol Ther (Heidelb) 2024; 14:1739-1753. [PMID: 38902589 PMCID: PMC11264500 DOI: 10.1007/s13555-024-01215-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 06/11/2024] [Indexed: 06/22/2024] Open
Abstract
Actinic keratosis (AK) is an intraepithelial condition characterized by the development of scaly, erythematous lesions after repeated exposure to ultraviolet radiation. Significant immunosuppression is a risk factor for the development of AK and subsequent lesion progression to squamous cell carcinoma. Immunocompromised patients (ICPs), particularly organ transplant recipients, often have more advanced or complex AK presentations and an increased risk of skin carcinomas versus non-ICPs with AK, making lesions more difficult to treat and resulting in worse treatment outcomes. The recent "Personalising Actinic Keratosis Treatment" (PAKT) consensus reported that delivering patient-centric care may play a role in supporting better clinical outcomes and patient satisfaction with treatments for chronic dermatologic conditions such as AK, which require repeated cycles of treatment. Additionally, currently published guidance and recommendations were considered by the PAKT panel to be overly broad for managing ICPs with their unique and complex needs. Therefore, the "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) panel was established to build upon general recommendations from the PAKT consensus. The panel identified current gaps in guidance for AK care in ICPs, offered practical care approaches based on typical ICP scenarios, and highlighted the need to adapt AK management to optimize care and improve treatment outcomes in ICPs. In particular, dermatologists should establish collaborative and transparent relationships with patients' multidisciplinary teams to enhance overall care for patients' comorbidities: given their increased risk of progression to malignancy, earlier assessments/interventions and frequent follow-ups are vital.The panel also developed a novel "triage" tool outlining effective treatment follow-up and disease surveillance plans tailored to patients' risk profiles, guided by current clinical presentation and relevant medical history. Additionally, we present the panel's expert opinion on three fictional ICP scenarios to explain their decision-making process for assessing and managing typical ICPs that they may encounter in clinical practice.
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Affiliation(s)
- Rolf-Markus Szeimies
- Department of Dermatology & Allergology, Klinikum Vest GmbH Academic Teaching Hospital, Recklinghausen, Germany.
| | - Claas Ulrich
- GmbH & Department of Dermatology, Collegium Medicum, Charité Universitätsmedizin, Berlin, Germany
| | - Carla Ferrándiz-Pulido
- Department of Dermatology, University Hospital Vall d'Hebron, Barcelona, Spain
- Factultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Gunther F L Hofbauer
- Universität Zürich, Zurich, Switzerland
- Dermatologische Klinik, Universitätsspital Zürich, Zurich, Switzerland
| | - John Thomas Lear
- Department of Dermatology, Mid Cheshire Hospitals NHS Foundation Trust, Crewe, UK
- Manchester Academic Health Science Centre, Manchester, UK
| | - Celeste Lebbé
- Dermato-Oncology and CIC AP-HP Hôpital Saint Louis, INSERM U976, Université Paris Cite, Paris, France
| | - Stefano Piaserico
- Dermatology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Merete Hædersdal
- Department of Dermatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Joo V, Abdelhamid K, Noto A, Latifyan S, Martina F, Daoudlarian D, De Micheli R, Pruijm M, Peters S, Hullin R, Gaide O, Pantaleo G, Obeid M. Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma. Nat Commun 2024; 15:3664. [PMID: 38693123 PMCID: PMC11063183 DOI: 10.1038/s41467-024-47965-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 04/15/2024] [Indexed: 05/03/2024] Open
Abstract
The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.
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Affiliation(s)
- Victor Joo
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Immunology and Allergy Division, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Karim Abdelhamid
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Alessandra Noto
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Immunology and Allergy Division, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Sofiya Latifyan
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Federica Martina
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Immunology and Allergy Division, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Douglas Daoudlarian
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Immunology and Allergy Division, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Rita De Micheli
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Menno Pruijm
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Nephrology Division, Rue du Bugnon 17, CH-1011, Lausanne, Switzerland
| | - Solange Peters
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Roger Hullin
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Cardiology, Cardiovascular Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Olivier Gaide
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Dermatology Division, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Giuseppe Pantaleo
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Immunology and Allergy Division, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland
| | - Michel Obeid
- Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Immunology and Allergy Division, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland.
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8
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Guo M, Pan C, Zhao Y, Xu W, Xu Y, Li D, Zhu Y, Cui X. Development of a Risk Prediction Model for Infection After Kidney Transplantation Transmitted from Bacterial Contaminated Preservation Solution. Infect Drug Resist 2024; 17:977-988. [PMID: 38505251 PMCID: PMC10949374 DOI: 10.2147/idr.s446582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 03/03/2024] [Indexed: 03/21/2024] Open
Abstract
Background The risk of transplant recipient infection is unknown when the preservation solution culture is positive. Methods We developed a prediction model to evaluate the infection in kidney transplant recipients within microbial contaminated preservation solution. Univariate logistic regression was utilized to identify risk factors for infection. Both stepwise selection with Akaike information criterion (AIC) was used to identify variables for multivariate logistic regression. Selected variables were incorporated in the nomograms to predict the probability of infection for kidney transplant recipients with microbial contaminated preservation solution. Results Age, preoperative creatinine, ESKAPE, PCT, hemofiltration, and sirolimus had a strongest association with infection risk, and a nomogram was established with an AUC value of 0.72 (95% confidence interval, 0.64-0.80) and Brier index 0.20 (95% confidence interval, 0.18-0.23). Finally, we found that when the infection probability was between 20% and 80%, the model oriented antibiotic strategy should have higher net benefits than the default strategy using decision curve analysis. Conclusion Our study developed and validated a risk prediction model for evaluating the infection of microbial contaminated preservation solutions in kidney transplant recipients and demonstrated good net benefits when the total infection probability was between 20% and 80%.
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Affiliation(s)
- Mingxing Guo
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Chen Pan
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Ying Zhao
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Wanyi Xu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Ye Xu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Dandan Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Yichen Zhu
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Xiangli Cui
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
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9
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Bakker D, Bakker WJ, Bekkenk MW, Luiten RM. Immunity against Non-Melanoma Skin Cancer and the Effect of Immunosuppressive Medication on Non-Melanoma Skin Cancer Risk in Solid Organ Transplant Recipients. Cells 2023; 12:2441. [PMID: 37887285 PMCID: PMC10605268 DOI: 10.3390/cells12202441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/22/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Non-melanoma skin cancers (NMSCs) occur frequently in the Caucasian population and are considered a burden for health care. Risk factors include ultraviolet (UV) radiation, ethnicity and immunosuppression. The incidence of NMSC is significantly higher in solid organ transplant recipients (SOTRs) than in immunocompetent individuals, due to immunosuppressive medication use by SOTRs. While the immunosuppressive agents, calcineurin inhibitors and purine analogues increase the incidence of NMSC in transplant recipients, mTOR inhibitors do not. This is most likely due to the different immunological pathways that are inhibited by each class of drug. This review will focus on what is currently known about the immune response against cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), two of the main types of NMSC. Furthermore, we will describe the different classes of immunosuppressants given to SOTRs, which part of the immune system they target and how they can contribute to NMSC development. The risk of developing NMSC in SOTRs is the result of a combination of inhibiting immunological pathways involved in immunosurveillance against NMSC and the direct (pro/anti) tumor effects of immunosuppressants.
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Affiliation(s)
- Dixie Bakker
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
| | - Walbert J. Bakker
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
| | - Marcel W. Bekkenk
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
- Amsterdam University Medical Centers, VU University of Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Rosalie M. Luiten
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
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10
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Fu C, Li X, Chen Y, Long X, Liu K. Lung cancer incidences after liver transplantation: A systematic review and meta-analysis. Cancer Med 2023; 12:16119-16128. [PMID: 37351559 PMCID: PMC10469810 DOI: 10.1002/cam4.6265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 05/30/2023] [Accepted: 06/06/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND Liver transplantation has made significant progress in recent decades. Lung cancer is one of the most frequently occurring cancers after liver transplantation. However, the risk of lung cancer among liver transplant patients compared with the general population is unclear. The aim of this meta-analysis was to assess the risk of developing lung cancer after liver transplantation. METHODS All eligible studies published in PubMed, Web of Science, and Embase from database inception to April 2022 were included. Standardized incidence ratio was used to describe the increased risk of lung cancer in liver transplant recipients as compared with the general population. The random-effects model was used for the calculations. A funnel plot and Egger test were performed to assess the potential publication bias. RESULTS Our meta-analysis included 15 studies, which involved 76,897 liver transplantation patients. Studies included in this review showed significant heterogeneity (I2 = 65.3%; p < 0.001), which required a random-effects model for effect pooling. The results indicated a significant higher risk of developing lung cancer in liver transplant patients than the general population with a pooled SIR of 2.06 (95% CI: 1.73, 2.46, p < 0.001). When stratified by region, no significant regional difference was observed. It showed a similarly doubled risk of lung cancer in Europe and North America, but an insignificantly increased risk in Asian populations. The sensitivity analysis by removal and substitution of each literature did not change the results. CONCLUSION Our meta-analysis suggests that liver transplant patients are twice as likely as the general population to develop lung cancer. Further research on risk factors for the development of lung cancer after liver transplantation should be conducted and appropriate surveillance protocols should be developed to reduce the risk of its occurrence.
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Affiliation(s)
- Chang Fu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery CenterFirst Hospital of Jilin UniversityChangchunChina
| | - Xiaocong Li
- Medical Research and Biometrics Center, National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yongjin Chen
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery CenterFirst Hospital of Jilin UniversityChangchunChina
| | - Xiaoyin Long
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery CenterFirst Hospital of Jilin UniversityChangchunChina
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery CenterFirst Hospital of Jilin UniversityChangchunChina
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11
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Cesario S, Genovesi V, Salani F, Vasile E, Fornaro L, Vivaldi C, Masi G. Evolving Landscape in Liver Transplantation for Hepatocellular Carcinoma: From Stage Migration to Immunotherapy Revolution. Life (Basel) 2023; 13:1562. [PMID: 37511937 PMCID: PMC10382048 DOI: 10.3390/life13071562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/30/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Liver transplantation (LT) represents the primary curative option for HCC. Despite the extension of transplantation criteria and conversion with down-staging loco-regional treatments, transplantation is not always possible. The introduction of new standards of care in advanced HCC including a combination of immune checkpoint inhibitor-based therapies led to an improvement in response rates and could represent a promising strategy for down-staging the tumor burden. In this review, we identify reports and series, comprising a total of 43 patients who received immune checkpoint inhibitors as bridging or down-staging therapies prior to LT. Overall, treated patients registered an objective response rate of 21%, and 14 patients were reduced within the Milan criteria. Graft rejection was reported in seven patients, resulting in the death of four patients; in the remaining cases, LT was performed safely after immunotherapy. Further investigations are required to define the duration of immune checkpoint inhibitors, their minimum washout period and the LT long-term safety of this strategy. Some randomized clinical trials including immunotherapy combinations, loco-regional treatment and/or tyrosine kinase inhibitors are ongoing and will likely determine the appropriateness of immune checkpoint inhibitors' administration before LT.
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Affiliation(s)
- Silvia Cesario
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Virginia Genovesi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Francesca Salani
- Institute of Interdisciplinary Research "Health Science", Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56124 Pisa, Italy
| | - Enrico Vasile
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Lorenzo Fornaro
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Gianluca Masi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
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12
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Xu G, Duan Z, Luo K, Yang J. Nanotherapeutics for solid organ transplantation: new kid on the block. EBioMedicine 2023; 92:104624. [PMID: 37209534 PMCID: PMC10209123 DOI: 10.1016/j.ebiom.2023.104624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 05/07/2023] [Indexed: 05/22/2023] Open
Affiliation(s)
- Gang Xu
- Liver Transplant Center, Organ Transplant Center, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China; Laboratory of Liver Transplantation, NHC Key Laboratory of Transplant Engineering and Immunology, Chengdu, 610041, China
| | - Zhenyu Duan
- Liver Transplant Center, Organ Transplant Center, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Kui Luo
- Liver Transplant Center, Organ Transplant Center, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China.
| | - Jiayin Yang
- Liver Transplant Center, Organ Transplant Center, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China; Laboratory of Liver Transplantation, NHC Key Laboratory of Transplant Engineering and Immunology, Chengdu, 610041, China.
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13
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Abstract
Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.
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14
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Ichimura H, Chino S, Shiba Y. Cardiac Regeneration Using Pluripotent Stem Cells and Controlling Immune Responses. Heart Lung Circ 2023:S1443-9506(23)00108-7. [PMID: 37029069 DOI: 10.1016/j.hlc.2022.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/02/2022] [Accepted: 12/05/2022] [Indexed: 04/08/2023]
Abstract
Pluripotent stem cell (PSC)-derived cardiomyocytes are a promising source of cells in myocardial regeneration therapy for end-stage heart failure. Because most previous reports have focussed on xenotransplantation models using immunocompromised animals, studies on immune rejection in allogeneic transplantation models are needed for preclinical and clinical applications. Human leukocyte antigen (HLA) plays an important role in allogeneic transplantation, and cell bank projects are currently underway worldwide to stock induced pluripotent stem cells (iPSCs) generated from healthy individuals with homozygous HLA haplotypes. However, it is difficult to stock iPSCs that match the entire population in these cell banks; thus, several groups have produced hypoimmunogenic PSCs by knocking out HLA. These HLA-knockout PSCs were able to avoid rejection by T cells but still suffered rejection by natural killer (NK) cells caused by 'missing self-recognition'. Recent studies have attempted to generate hypoimmunogenic PSCs with gene editing to inhibit NK cell activation. Regenerative medicine using autologous iPSCs can be an ideal transplantation therapy, but, currently, there are major hurdles to its practical application. Hopefully, further research will resolve these issues. This review provides an overview of the current understanding and progress in this field.
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Affiliation(s)
- Hajime Ichimura
- Department of Regenerative Science and Medicine, Shinshu University School of Medicine, Matsumoto, Japan; Department of Surgery, Division of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shuji Chino
- Department of Surgery, Division of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuji Shiba
- Department of Regenerative Science and Medicine, Shinshu University School of Medicine, Matsumoto, Japan; Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.
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15
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Belčič Mikič T, Mlinšek G, Oblak M, Kandus A, Buturović-Ponikvar J, Hawlina S, Milanez T, Kojc N, Frelih M, Arnol M. Transmission of pancreatic adenocarcinoma by a single multiorgan donor to two kidney transplant recipients: A case report. Front Med (Lausanne) 2023; 10:1142611. [PMID: 36999065 PMCID: PMC10046802 DOI: 10.3389/fmed.2023.1142611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 02/17/2023] [Indexed: 03/17/2023] Open
Abstract
We present two cases of transmission of a pancreatic adenocarcinoma from a single donor to two kidney transplant recipients. Autopsy of the donor revealed a pancreatic adenocarcinoma that had already spread locally to the regional lymph nodes and had not been detected at the time of organ procurement. Both recipients were carefully monitored, as neither consented to graft nephrectomy. In one patient, the tumor was discovered on surveillance biopsy of the graft approximately 14 months after transplantation, and in the second patient, ultrasound-guided aspiration needle biopsy of a growing formation in the lower pole of the graft revealed poorly differentiated metastatic adenocarcinoma. Both patients were successfully treated with graft nephrectomy and complete discontinuation of immunosuppression. None of the follow-up imaging showed persistent or recurrent malignancy, and both patients were candidates for re-transplantation. These exceptional cases of donor-derived pancreatic adenocarcinoma suggest that removal of the donor organ and restoration of immunity may lead to complete recovery.
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Affiliation(s)
- Tanja Belčič Mikič
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Gregor Mlinšek
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Manca Oblak
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Aljoša Kandus
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Jadranka Buturović-Ponikvar
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Simon Hawlina
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Urology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tomaž Milanez
- Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Nika Kojc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Maja Frelih
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Miha Arnol
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- *Correspondence: Miha Arnol,
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16
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Targeting Breast Cancer: An Overlook on Current Strategies. Int J Mol Sci 2023; 24:ijms24043643. [PMID: 36835056 PMCID: PMC9959993 DOI: 10.3390/ijms24043643] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Breast cancer (BC) is one of the most widely diagnosed cancers and a leading cause of cancer death among women worldwide. Globally, BC is the second most frequent cancer and first most frequent gynecological one, affecting women with a relatively low case-mortality rate. Surgery, radiotherapy, and chemotherapy are the main treatments for BC, even though the latter are often not aways successful because of the common side effects and the damage caused to healthy tissues and organs. Aggressive and metastatic BCs are difficult to treat, thus new studies are needed in order to find new therapies and strategies for managing these diseases. In this review, we intend to give an overview of studies in this field, presenting the data from the literature concerning the classification of BCs and the drugs used in therapy for the treatment of BCs, along with drugs in clinical studies.
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17
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Palmieri R, Montgomery RB, Doney K. Allogeneic stem cell transplantation in patients with a prior history of prostate cancer. Ann Hematol 2023; 102:407-412. [PMID: 36394580 DOI: 10.1007/s00277-022-05041-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 11/08/2022] [Indexed: 11/18/2022]
Abstract
A retrospective analysis of 25 patients with a history of prostate cancer (PC) who subsequently underwent allogeneic hematopoietic cell transplantation (HCT) for treatment of a hematologic malignancy was performed. Median patient age was 66.7 years. Median duration from the diagnosis of PC to HCT was 4.2 years. Twenty-three patients had Gleason group 1 or 2 disease. Therapy included prostatectomy (n = 13) and external beam or brachytherapy (n = 9). Hematologic diagnoses included both myeloid (n = 15) and lymphoid neoplasms (n = 10). Twenty-four patients received either a nonmyeloablative or reduced intensity conditioning regimen. GVHD prophylaxis included a calcineurin inhibitor and mycophenolate mofetil ± sirolimus. Twenty patients had HLA-matched sibling or HLA-matched unrelated donors; five patients had HLA-mismatched donors. Eleven patients are alive, and 14 have died. Median survival was 2.5 years (range, .02-12.6 years). The major cause of death was hematologic relapse. Only one patient had evidence of recurrent PC, occurring 1.5 years posttransplant. In carefully selected patients with a prior history of PC, there was no evidence of rapid recurrence of the solid tumor (ST) after HCT. PC patients who are in remission from their ST or have control of their disease on therapy should be considered eligible for HCT.
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Affiliation(s)
- Raffaele Palmieri
- Clinical Research Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave. N., D5-280, PO Box 19024, Seattle, WA, 98109-1024, USA.,Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Robert B Montgomery
- Department of Medicine, Division of Oncology, University of Washington Medical Center, Seattle, WA, USA.,VA Puget Sound, Seattle, WA, USA
| | - Kristine Doney
- Clinical Research Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave. N., D5-280, PO Box 19024, Seattle, WA, 98109-1024, USA. .,Department of Medicine, Division of Oncology, University of Washington Medical Center, Seattle, WA, USA.
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18
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Hart A, Pfeiffer RM, Morawski BM, Lynch CF, Zeng Y, Pawlish K, Hurley D, Yu KJ, Engels EA. Mortality among solid organ transplant recipients with a pretransplant cancer diagnosis. Am J Transplant 2023; 23:257-264. [PMID: 36804133 PMCID: PMC9978936 DOI: 10.1016/j.ajt.2022.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/10/2022] [Accepted: 11/08/2022] [Indexed: 01/15/2023]
Abstract
Little is known about the outcomes among solid organ transplant recipients with a pretransplant cancer diagnosis. We used linked data from the Scientific Registry of Transplant Recipients with 33 US cancer registries. Cox proportional hazards models assessed associations of pretransplant cancer with overall mortality, cancer-specific mortality, and development of a new posttransplant cancer. Among 311 677 recipients, the presence of a single pretransplant cancer was associated with increased overall mortality (adjusted hazard ratio [aHR], 1.19; 95% CI, 1.15-1.23) and cancer-specific mortality (aHR, 1.93; 95% CI, 1.76-2.12); results for 2+ pretransplant cancers were similar. Cancer-specific mortality was not significantly increased for uterine, prostate, or thyroid cancers (aHRs were 0.83, 1.22, and 1.54, respectively) but strongly elevated for lung cancer and myeloma (aHRs were 3.72 and 4.42, respectively). A pretransplant cancer diagnosis was also associated with increased risk of developing posttransplant cancer (aHR, 1.32; 95% CI, 1.23-1.40). Among 306 recipients whose cancer death was confirmed by cancer registry data, 158 deaths (51.6%) were from a de novo posttransplant cancer and 105 (34.3%) from the pretransplant cancer. Pretransplant cancer diagnoses are associated with increased mortality after transplantation, but some deaths are related to posttransplant cancers and other causes. Improved candidate selection and cancer screening and prevention may reduce mortality in this population.
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Affiliation(s)
- Allyson Hart
- Scientific Registry of Transplant Recipients, Minneapolis, Minnesota, USA.
| | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Bozena M Morawski
- Cancer Data Registry of Idaho, Idaho Hospital Association, Boise, Idaho, USA
| | - Charles F Lynch
- University of Iowa Department of Epidemiology, Iowa City, Iowa, USA
| | - Yun Zeng
- University of North Dakota Department of Pathology, North Dakota Statewide Cancer Registry, Grand Forks, North Dakota, USA
| | - Karen Pawlish
- New Jersey State Cancer Registry, New Jersey Department of Health, Trenton, New Jersey, USA
| | - Deborah Hurley
- South Carolina Central Cancer Registry Bureau of Chronic Disease & Injury Prevention, Columbia, South Carolina, USA
| | - Kelly J Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
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19
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Panackel C, Mathew JF, Fawas N M, Jacob M. Immunosuppressive Drugs in Liver Transplant: An Insight. J Clin Exp Hepatol 2022; 12:1557-1571. [PMID: 36340316 PMCID: PMC9630030 DOI: 10.1016/j.jceh.2022.06.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/16/2022] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is the standard of care for end-stage liver failure and hepatocellular carcinoma. Over the years, immunosuppression regimens have improved, resulting in enhanced graft and patient survival. At present, the side effects of immunosuppressive agents are a significant threat to post-LT quality of life and long-term outcome. The role of personalized immunosuppression is to reach a delicate balance between optimal immunosuppression and minimal side effects. Today, immunosuppression in LT is more of an art than a science. There are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring and immunosuppression regimens vary from center to center. The immunosuppressive agents are broadly classified into biological agents and pharmacological agents. Most regimens use multiple agents with different modes of action to reduce the dosage and minimize the toxicities. The calcineurin inhibitor (CNI)-related toxicities are reduced by antibody induction or using mTOR inhibitor/antimetabolites as CNI sparing or CNI minimization strategies. Post-liver transplant immunosuppression has an intensive phase in the first three months when alloreactivity is high, followed by a maintenance phase when immunosuppression minimization protocols are implemented. Over time some patients achieve "tolerance," defined as the successful stopping of immunosuppression with good graft function and no indication of rejection. Cell-based therapy using immune cells with tolerogenic potential is the future and may permit complete withdrawal of immunosuppressive agents.
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Key Words
- AMR, Antibody-mediated rejection
- APCs, Antigen-presenting cells
- ATG, Anti-thymocyte globulin
- CNI, Calcineurin inhibitors
- CsA, Cyclosporine A
- EVR, Everolimus
- IL-2R, Interleukin 2 Receptor
- LT, Liver transplantation
- MMF, Mycophenolate mofetil
- MPA, Mycophenolic acid
- SRL, Sirolimus
- TAC, Tacrolimus
- TCMR, T-cell-mediated rejection
- antimetabolites
- basiliximab
- calcineurin inhibitors
- cyclosporine
- everolimus
- immunosuppression
- liver transplantation
- mTORi, mammalian targets of rapamycin inhibitor
- mycophenolate mofetil
- tacrolimus
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Affiliation(s)
- Charles Panackel
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Joe F Mathew
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Mohamed Fawas N
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Mathew Jacob
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
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20
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Therapeutic Antiaging Strategies. Biomedicines 2022; 10:biomedicines10102515. [PMID: 36289777 PMCID: PMC9599338 DOI: 10.3390/biomedicines10102515] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/21/2022] [Accepted: 09/24/2022] [Indexed: 11/17/2022] Open
Abstract
Aging constitutes progressive physiological changes in an organism. These changes alter the normal biological functions, such as the ability to manage metabolic stress, and eventually lead to cellular senescence. The process itself is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks are risk factors for pathologies, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Emerging evidence has been focused on examining the genetic pathways and biological processes in organisms surrounding these nine hallmarks. From here, the therapeutic approaches can be addressed in hopes of slowing the progression of aging. In this review, data have been collected on the hallmarks and their relative contributions to aging and supplemented with in vitro and in vivo antiaging research experiments. It is the intention of this article to highlight the most important antiaging strategies that researchers have proposed, including preventive measures, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects.
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21
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Gonzalez-Alcocer A, Gopar-Cuevas Y, Soto-Dominguez A, Loera-Arias MDJ, Saucedo-Cardenas O, Montes de Oca-Luna R, Rodriguez-Rocha H, Garcia-Garcia A. Peripheral tissular analysis of rapamycin's effect as a neuroprotective agent in vivo. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1239-1255. [PMID: 35895156 DOI: 10.1007/s00210-022-02276-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/15/2022] [Indexed: 10/16/2022]
Abstract
Rapamycin is the best-characterized autophagy inducer, which is related to its antiaging and neuroprotective effects. Although rapamycin is an FDA-approved drug for human use in organ transplantation and cancer therapy, its administration as an antiaging and neuroprotective agent is still controversial because of its immunosuppressive and reported side effects. Therefore, it is critical to determine whether the dose that exerts a neuroprotective effect, 35 times lower than that used as an immunosuppressant agent, harms peripheral organs. We validated the rapamycin neuroprotective dosage in a Parkinson's disease (PD) model induced with paraquat. C57BL/6 J mice were treated with intraperitoneal (IP) rapamycin (1 mg/kg) three times per week, followed by paraquat (10 mg/kg) twice per week for 6 weeks, along with rapamycin on alternate days. Rapamycin significantly decreased dopaminergic neuronal loss induced by paraquat. Since rapamycin's neuroprotective effect in a PD model was observed at 7 weeks of treatment; we evaluated its effect on the liver, kidney, pancreas, and spleen. In addition, we prolonged treatment with rapamycin for 14 weeks. Tissue sections were subjected to histochemical, immunodetection, and morphometric analysis. Chronic rapamycin administration does not affect bodyweight, survival, and liver or kidney morphology. Although the pancreas tissular architecture and cellular distribution in Langerhans islets are modified, they may be reversible. The spleen B lymphocyte and macrophage populations were decreased. Notably, the lymphocyte T population was not affected. Therefore, chronic administration of a rapamycin neuroprotective dose does not produce significant tissular alterations. Our findings support the therapeutic potential of rapamycin as a neuroprotective agent.
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Affiliation(s)
- Alfredo Gonzalez-Alcocer
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Yareth Gopar-Cuevas
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Adolfo Soto-Dominguez
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Maria de Jesus Loera-Arias
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Odila Saucedo-Cardenas
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Roberto Montes de Oca-Luna
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Humberto Rodriguez-Rocha
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Aracely Garcia-Garcia
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México.
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22
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Serkies K, Dębska-Ślisień A, Kowalczyk A, Lizakowski S, Małyszko J. Malignancies in adult kidney transplant candidates and recipients: current status. Nephrol Dial Transplant 2022:6674222. [PMID: 35998321 DOI: 10.1093/ndt/gfac239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Posttransplant malignancies, particularly recurrent and de novo, in solid organs including kidney transplant recipients (KTRs) are a significant complication associated with substantial mortality, largely attributed to long-term immunosuppression necessary to maintain allograft tolerance. Older age at transplantation and oncogenic virus infection along with pretransplant malignancies are among the main factors contributing to the risk of cancer in this population. As the mean age of transplant candidates rises, the rate of transplant recipients with pretransplant malignancies also increases. The eligibility criteria for transplantation in patients with prior cancer have recently changed. The overall risk of posttransplant malignancies is at least double after transplantation including KTRs relative to the general population, most pronounced for skin cancers associated with UV radiation and virally-mediated tumors. The risk of renal cell carcinoma is specifically increased in the kidney transplant population. The therapy of cancer in transplant patients is associated with risk of higher toxicity, and graft rejection and/or impairment, which poses a unique challenge in the management. Reduction of immunosuppression and the use of mTOR inhibitors are common after cancer diagnosis, although optimal immunosuppression for transplant recipients with cancer remains undefined. Suboptimal cancer treatment contributing to a worse prognosis has been reported for malignancies in this population. In this article, we focus on the prevalence and outcomes of posttransplant malignancies, cancer therapy including a short overview of immunotherapy, cancer screening and prevention strategies, and immunosuppression as a cancer risk factor. The 2020/2021 recommendations of the Kidney Diseases Improving Global Outcome (KDIGO) and American Society of Transplantation (AST) for transplant candidates with a history of cancer are presented.
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Affiliation(s)
- Krystyna Serkies
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Poland
| | - Alicja Dębska-Ślisień
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland
| | - Anna Kowalczyk
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Poland
| | - Sławomir Lizakowski
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland
| | - Jolanta Małyszko
- Department of Nephrology, Dialysis and Internal Medicine, Warsaw Medical University, Poland
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23
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O'Shea AE, Valdera FA, Ensley D, Smolinsky TR, Cindass JL, Kemp Bohan PM, Hickerson AT, Carpenter EL, McCarthy PM, Adams AM, Vreeland TJ, Clifton GT, Peoples GE. Immunologic and dose dependent effects of rapamycin and its evolving role in chemoprevention. Clin Immunol 2022; 245:109095. [PMID: 35973640 DOI: 10.1016/j.clim.2022.109095] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/06/2022] [Indexed: 11/29/2022]
Abstract
Rapamycin inhibits the mechanistic (formally mammalian) target of rapamycin (mTOR), an evolutionarily conserved intracellular kinase that influences activation of growth signaling pathways and immune responses to malignancy. Rapamycin has been found to have both immunosuppressant and immunostimulatory effects throughout the innate and adaptive responses based on the inhibition of mTOR signaling. While the immunosuppressant properties of rapamycin and mTOR inhibition explain rapamycin's success in the prevention of transplant rejection, the immunostimulatory characteristics are likely partially responsible for rapamycin's anti-neoplastic effects. The immunologic response to rapamycin is at least partially dependent on the dose and administration schedule, with lower doses inducing immunostimulation and intermittent dosing promoting immune function while limiting metabolic and immunosuppressant toxicities. In addition to its FDA-approved application in advanced malignancies, rapamycin may be effective as a chemopreventive agent, suspending progression of low-grade cancers, preventing invasive conversion of in situ malignancy, or delaying malignant transformation of established pre-malignant conditions.
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Affiliation(s)
- Anne E O'Shea
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | - Franklin A Valdera
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, USA.
| | - Daniel Ensley
- Department of Urology, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | - Todd R Smolinsky
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | - Jessica L Cindass
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | | | | | | | - Patrick M McCarthy
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | - Alexandra M Adams
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | - Timothy J Vreeland
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, USA; Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Guy T Clifton
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, USA; Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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24
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Nelson J, Alvey N, Bowman L, Schulte J, Segovia M, McDermott J, Te HS, Kapila N, Levine DJ, Gottlieb RL, Oberholzer J, Campara M. Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation. Pharmacotherapy 2022; 42:599-633. [DOI: 10.1002/phar.2716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/29/2022] [Accepted: 04/08/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Joelle Nelson
- Department of Pharmacotherapy and Pharmacy Services University Health San Antonio Texas USA
- Pharmacotherapy Education and Research Center University of Texas Health San Antonio San Antonio Texas USA
- Department of Pharmacy, Pharmacotherapy Division, College of Pharmacy The University of Texas at Austin Austin Texas USA
| | - Nicole Alvey
- Department of Pharmacy Rush University Medical Center Chicago Illinois USA
- Science and Pharmacy Roosevelt University College of Health Schaumburg Illinois USA
| | - Lyndsey Bowman
- Department of Pharmacy Tampa General Hospital Tampa Florida USA
| | - Jamie Schulte
- Department of Pharmacy Services Thomas Jefferson University Hospital Philadelphia Pennsylvania USA
| | | | - Jennifer McDermott
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health Grand Rapids Michigan USA
- Department of Medicine, Michigan State University College of Human Medicine Grand Rapids Michigan USA
| | - Helen S. Te
- Liver Transplantation, Center for Liver Diseases, Department of Medicine University of Chicago Medical Center Chicago Illinois USA
| | - Nikhil Kapila
- Department of Transplant Hepatology Duke University Hospital Durham North Carolina USA
| | - Deborah Jo Levine
- Division of Critical Care Medicine, Department of Medicine The University of Texas Health Science Center at San Antonio San Antonio Texas USA
| | - Robert L. Gottlieb
- Baylor University Medical Center and Baylor Scott and White Research Institute Dallas Texas USA
| | - Jose Oberholzer
- Department of Surgery/Division of Transplantation University of Virginia Charlottesville Virginia USA
| | - Maya Campara
- Department of Surgery University of Illinois Chicago Chicago Illinois USA
- Department of Pharmacy Practice University of Illinois Chicago Chicago Illinois USA
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25
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Gluck M, Hodak E, Davidovici B. Mammalian Target of Rapamycin Inhibitors for prolonged secondary prevention of non-melanoma skin cancer in solid organ transplant recipients. Dermatol Ther 2022; 35:e15649. [PMID: 35716099 DOI: 10.1111/dth.15649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 05/30/2022] [Accepted: 06/16/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Immunosuppressive agents are essential for graft survival in solid-organ transplant recipients (SOTRs), but they have substantial durable side effects, including a higher incidence of aggressive non-melanoma skin cancers (NMSCs). Hitherto, only one class of immunosuppressants, mammalian target of rapamycin inhibitors (mTORi), may inhibit skin tumor formation, however their durable effectiveness is controversial. OBJECTIVE To evaluate the sustained effectiveness of mTORi in reducing NMSCs' incidence in SOTRs. METHODS A retrospective study was conducted in a specialized dermatology clinic for SOTRs of a tertiary university-affiliated medical center. SOTRs with a history of at least one histologically proven NMSC, were followed for 6 years: 3 years after transplantation, before initiation of mTORi, and 3 years under mTORi treatment. RESULTS The cohort consisted of 44 SOTRs. Treatment with mTORi was initiated on average 6.27 (3.34-6.34) years following transplantation. In the 3 years before mTORi treatment initiation, the mean number of new NMSCs per patient was 2.11 (1-14). This value decreased to 1.2 (0-19) in the 3 years under mTORi treatment (P=0.0007). Analysis by NMSC type yielded a significant decrease in both SCCs and BCCs. CONCLUSION This study found that mTORi are effective for prolonged secondary prevention of NMSCs in SOTRs. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Mirit Gluck
- Devision of Dermatology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Emmillia Hodak
- Devision of Dermatology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Batya Davidovici
- Devision of Dermatology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
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26
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Karatas M, Okut G, Simsek C, Dogan SM, Zengel B, Taslı Alkan F, Tatar E. Genitourinary Cancers Following Kidney Transplant: Our 20 Years of Experience With Mechanistic Target of Rapamycin Inhibitors. EXP CLIN TRANSPLANT 2022; 20:145-148. [PMID: 35384826 DOI: 10.6002/ect.mesot2021.p72] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES We investigated patients with genitourinary cancer after kidney transplant and the effects of immunosuppression reduction and switching to mechanistic target of rapamycin inhibitors. MATERIALS AND METHODS We retrospectively evaluated kidney transplant recipients seen at our center between January 2000 and January 2020. Patients with <1 year of follow-up were excluded. RESULTS Of 827 patients, genitourinary cancer was detected in 11 (1.3%): prostate cancer in 5 patients (45%), renal cell carcinoma in native kidney in 3 (27%), renal cell carcinoma in allograft kidney in 2 (18%), and transitional cell carcinoma of the bladder in 1 (9%). All patients had surgery. Two patients had bone metastasis due to prostate cancer at diagnosis. Two patients had allograft nephrectomy due to de novo renal cell carcinoma. Mean follow-up and age were 97 ± 45 months (range, 26-189) and 50 ± 10.2 years (19% female). After cancer diagnosis, excluding the 2 patients with allograft nephrectomy, immunosuppression was changed in 8 patients (88.8%) (1 patient received the same treatment before and after cancer diagnosis). Six patients received double-drug and 3 received triple-drug protocols. Of 9 patients, 2 were already using mechanistic target of rapamycin inhibitors before cancer diagnosis and 7 were switched: 4 to double-based and 3 to triple-based regimens. Six were switched from tacrolimus. With new treatments, patients showed no progressive kidney failure or rejection (38 ± 40 mo average follow-up). At last follow-up, mean glomerular filtration rate was 62.8 ± 34 mL/min/1.72 m2, which was similar to rate at cancer diagnosis (58.9 ± 24 mL/ min/1.72 m2; P = .78). During follow-up, no patients developed local recurrence of primary tumor or new metastasis, and none showed adverse effects after switch to mechanistic target of rapamycin inhibitors. Three patients died of malignancy-unrelated reasons (ileus, urinary sepsis, heart failure). CONCLUSIONS Mechanistic target of rapamycin inhibitor-based drugs can be an important maintenance immunosuppressive treatment option for kidney transplant recipients with genitourinary cancers.
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Affiliation(s)
- Murat Karatas
- From the Department of General Surgery and Transplantation, University of Health Sciences, Izmir Faculty of Medicine, Bozyaka Education and Research Hospital, Izmir, Turkey
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27
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Kobayashi T, Miura K, Ishikawa H, Toge K, Hirose Y, Takizawa K, Sakata J, Wakai T, Ishiguro T, Kudo R, Enomoto T, Saito K, Tasaki M, Ikeda M, Tomita Y, Kinoshita Y. Endometrial Cancer After Pancreas-After-Kidney Transplantation: A Case Report and Review of the Literature. Transplant Proc 2022; 54:560-564. [PMID: 35067377 DOI: 10.1016/j.transproceed.2021.12.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 12/29/2021] [Indexed: 01/20/2023]
Abstract
BACKGROUND As the number of long-term survivors after organ transplantation increases, malignancy has become a problem as a late complication. We herein report a case of endometrial cancer during the follow-up of pancreas transplantation after kidney transplantation. CASE PRESENTATION A 49-year-old woman was diagnosed with endometrial cancer. The patient had developed type 1 diabetes at 8 years old and started insulin treatment, and at 29 years old, she started hemodialysis for diabetic nephropathy. At 31 years old, she received living donor kidney transplantation and withdrew from dialysis. Hypoglycemia unawareness began to occur frequently from around 36 years old, and at 48 years old, the patient underwent deceased donor pancreas transplantation after kidney transplantation and achieved insulin independence. At 49 years old, she was diagnosed with endometrial cancer. Surgical treatment (total abdominal hysterectomy with left salpingo-oophorectomy) was performed. The pathologic diagnosis was confirmed as stage 1A uterine endometrioid carcinoma grade 1. The postoperative course was uneventful. She was discharged from our hospital on postoperative day 8. There has been no evidence of recurrence and/or metastasis of endometrial cancer for 16 months since the surgery. CONCLUSIONS Carcinogenesis after pancreas transplantation may be a lethal late complication. It is important to carry out regular screening examinations with carcinogenesis in mind.
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Affiliation(s)
- Takashi Kobayashi
- Department of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Kohei Miura
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hirosuke Ishikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Koji Toge
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuki Hirose
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kazuyasu Takizawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Jun Sakata
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tatsuya Ishiguro
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Risa Kudo
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takayuki Enomoto
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kazuhide Saito
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masayuki Tasaki
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masahiro Ikeda
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yoshihiko Tomita
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yoshiaki Kinoshita
- Department of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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28
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Toniutto P, Germani G, Ferrarese A, Bitetto D, Zanetto A, Fornasiere E, Fumolo E, Shalaby S, Burra P. An Essential Guide for Managing Post-Liver Transplant Patients: What Primary Care Physicians Should Know. Am J Med 2022; 135:157-166. [PMID: 34508700 DOI: 10.1016/j.amjmed.2021.08.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 12/16/2022]
Abstract
With long-term survival after liver transplantation becoming the rule, care for medical problems arising over time in liver-transplanted patients gained increasing importance. The most common causes of death occurring more than 1 year after liver transplantation are unrelated to liver diseases and facilitated by immunosuppressive treatments; examples are malignancies, renal failure, and cardiovascular, metabolic, and infectious diseases. Recipients receive life-long follow-up care at transplant centers, however, the increasing number of liver-transplanted patients is saturating the health care supply that transplant centers have to offer. Primary care physicians are increasingly exposed to liver-transplanted patients, even in the early periods after transplant, and an understanding of the most common risks and complications faced by these patients would enhance their care. This article reviews the long-term care of liver transplant recipients, emphasizing the key internal medicine-related issues that should be known by primary care physicians. A specific section is devoted to implementing strategies to involve these physicians in the long-term follow-up of liver-transplanted patients in close collaboration with transplant hepatologists.
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Affiliation(s)
- Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Department of Specialized Medicine, Udine University Hospital, Udine, Italy;.
| | - Giacomo Germani
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Alberto Ferrarese
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Davide Bitetto
- Hepatology and Liver Transplantation Unit, Department of Specialized Medicine, Udine University Hospital, Udine, Italy
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Ezio Fornasiere
- Hepatology and Liver Transplantation Unit, Department of Specialized Medicine, Udine University Hospital, Udine, Italy
| | - Elisa Fumolo
- Hepatology and Liver Transplantation Unit, Department of Specialized Medicine, Udine University Hospital, Udine, Italy
| | - Sarah Shalaby
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
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29
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Imamura R, Tanaka R, Taniguchi A, Nakazawa S, Kato T, Yamanaka K, Namba-Hamano T, Kakuta Y, Abe T, Tsutahara K, Takao T, Kishikawa H, Nonomura N. Everolimus Reduces Cancer Incidence and Improves Patient and Graft Survival Rates after Kidney Transplantation: A Multi-Center Study. J Clin Med 2022; 11:249. [PMID: 35011990 PMCID: PMC8746009 DOI: 10.3390/jcm11010249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation can prevent renal failure and associated complications in patients with end-stage renal disease. Despite the good quality of life, de novo cancers after kidney transplantation are a major complication impacting survival and there is an urgent need to establish immunosuppressive protocols to prevent de novo cancers. We conducted a multi-center retrospective study of 2002 patients who underwent kidney transplantation between 1965 and 2020 to examine patient and graft survival rates and cumulative cancer incidence in the following groups categorized based on specific induction immunosuppressive therapies: group 1, antiproliferative agents and steroids; group 2, calcineurin inhibitors (CNIs), antiproliferative agents and steroids; group 3, CNIs, mycophenolate mofetil, and steroids; and group 4, mammalian target of rapamycin inhibitors including everolimus, CNIs, mycophenolate mofetil, and steroids. The patient and graft survival rates were significantly higher in groups 3 and 4. The cumulative cancer incidence rate significantly increased with the use of more potent immunosuppressants, and the time to develop cancer was shorter. Only one patient in group 4 developed de novo cancer. Potent immunosuppressants might improve graft survival rate while inducing de novo cancer after kidney transplantation. Our data also suggest that everolimus might suppress cancer development after kidney transplantation.
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Affiliation(s)
- Ryoichi Imamura
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Ryo Tanaka
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Ayumu Taniguchi
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Shigeaki Nakazawa
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Taigo Kato
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Kazuaki Yamanaka
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Tomoko Namba-Hamano
- Department of Nephrology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
| | - Yoichi Kakuta
- Osaka General Medical Center, Department of Urology, Osaka 558-8558, Japan; (Y.K.); (K.T.); (T.T.)
| | - Toyofumi Abe
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Koichi Tsutahara
- Osaka General Medical Center, Department of Urology, Osaka 558-8558, Japan; (Y.K.); (K.T.); (T.T.)
| | - Tetsuya Takao
- Osaka General Medical Center, Department of Urology, Osaka 558-8558, Japan; (Y.K.); (K.T.); (T.T.)
| | - Hidefumi Kishikawa
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya 662-0918, Japan;
| | - Norio Nonomura
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
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30
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Sutaria N, Sylvia L, DeNofrio D. Immunosuppression and Heart Transplantation. Handb Exp Pharmacol 2021; 272:117-137. [PMID: 34671867 DOI: 10.1007/164_2021_552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Since the first human heart transplant in 1967, immense advancements have been made in the field of immunosuppression. This chapter provides an in-depth analysis of the use of immunosuppressive agents in heart transplant recipients. Evidence regarding maintenance immunosuppressive regimens, the efficacy of induction immunosuppression and corticosteroid weaning, as well as the use of distinct immunosuppression regimens within select patient populations is summarized. This chapter helps elucidate the data regarding contemporary protocols in cardiac transplantation.
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Affiliation(s)
- Nilay Sutaria
- Cardiovascular Center, Tufts Medical Center, Boston, MA, USA
| | - Lynne Sylvia
- Cardiovascular Center, Tufts Medical Center, Boston, MA, USA
| | - David DeNofrio
- Cardiovascular Center, Tufts Medical Center, Boston, MA, USA.
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31
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Tabbara MM, Al Nuss MA, Chandar JJ, Alperstein W, Ciancio G. Treatment of allograft renal cell carcinoma with partial nephrectomy in a pediatric kidney transplant. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2021; 73. [PMID: 34993052 PMCID: PMC8730291 DOI: 10.1016/j.epsc.2021.102018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Renal cell carcinoma (RCC) is a common malignancy among kidney transplant recipients that often occurs in the native kidney. The incidence of RCC in the renal allograft is rare and carries the double risk of returning to dialysis and the development of metastatic cancer. The majority of reported cases of RCC in transplanted kidneys are in adult recipients and its occurrence in the pediatric age group is an uncommon event. There are currently no established guidelines on the treatment of RCC in transplant recipients. We report our experience of a 15-year-old male who developed allograft RCC 12 years later after transplantation. MRI confirmed the presence of the mass near the hilum of the renal allograft and biopsy revealed a Papillary Renal Cell Carcinoma (PRCC) type I. A partial allograft nephrectomy was successfully performed with negative tumor margins. The patient’s serum creatinine 12 months post-operation was 1.9 mg/dL and presently he has no evidence of residual disease, recurrence, or metastasis. Partial nephrectomy is an effective treatment option for renal allograft RCC as it spares the patient from returning to dialysis until retransplantation is possible and necessary.
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Affiliation(s)
| | | | - Jayanthi J. Chandar
- Pediatrics, Division of Pediatric Nephrology, USA
- Miami Transplant Institute, USA
| | - Warren Alperstein
- Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, USA
| | - Gaetano Ciancio
- Department of Surgery, USA
- Urology, USA
- Miami Transplant Institute, USA
- University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
- Corresponding author. University of Miami Miller School of Medicine Department of Surgery and Urology, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami FL Miami Transplant Institute 1801 NW 9th Ave, 7th Floor, Miami, FL, 33136, USA. (G. Ciancio)
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32
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Schaper-Gerhardt K, Hansel A, Walter A, Grimmelmann I, Gutzmer R. Sirolimus diminishes the expression of GRO-α (CXCL-1) /CXCR2 axis in human keratinocytes and cutaneous squamous cell carcinoma cells. J Dermatol Sci 2021; 104:30-38. [PMID: 34479772 DOI: 10.1016/j.jdermsci.2021.08.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 08/13/2021] [Accepted: 08/24/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Organ transplant recipients show a high incidence for the formation of cutaneous squamous cell carcinoma (cSCC), while sirolimus appears to reduce the risk. GRO-α is a chemokine, which is overexpressed in many tumor entities and associated with malignant transformation. However, little is known about the expression and function of GRO-α in human cSCC. OBJECTIVE Our aim was to investigate the relevance of the GRO-α (CXCL-1)/ CXCR2 axis in human cSCC and the potential impact of sirolimus. METHODS We analyzed the GRO-α expression in human keratinocytes, different cSCC cell lines as well as cSCC tissue and investigated its effect on cell proliferation and migration. Additionally, we incubated cells with sirolimus and measured the expression of GRO-α and its receptor CXCR2. RESULTS We showed that both constitutive as well as induced GRO-α expression is higher in in cSCC cell lines compared to keratinocytes and that GRO-α protein is detectable in human cSCC tissue. By GRO-α exposure and shRNA knock down, we identified GRO-α as a driving factor in proliferation and migration. Moreover, in a dermis equivalent GRO-α knocked down cSCC cell lines displayed a reduced capacity in tumor nest formation. Incubation with sirolimus significantly inhibited GRO-α expression in keratinocytes as well as tumor cell lines. Moreover, sirolimus decreased the expression of the corresponding receptor CXCR2. CONCLUSION Taken together, our results suggest that the GRO-α/CXCR2 axis plays a role in human keratinocyte carcinogenesis and might represent a molecular mechanism for the preventive effect of mTOR inhibitors in cSCC development.
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Affiliation(s)
- Katrin Schaper-Gerhardt
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany; Department of Dermatology, Ruhr University Bochum, Campus Minden, Minden, Germany.
| | - Annika Hansel
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - Antje Walter
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - Imke Grimmelmann
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - Ralf Gutzmer
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany; Department of Dermatology, Ruhr University Bochum, Campus Minden, Minden, Germany
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Wojciechowski D, Wiseman A. Long-Term Immunosuppression Management: Opportunities and Uncertainties. Clin J Am Soc Nephrol 2021; 16:1264-1271. [PMID: 33853841 PMCID: PMC8455033 DOI: 10.2215/cjn.15040920] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5-8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor-based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.
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Affiliation(s)
- David Wojciechowski
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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Lentine KL, Cheungpasitporn W, Xiao H, McAdams-DeMarco M, Lam NN, Segev DL, Bae S, Ahn JB, Hess GP, Caliskan Y, Randall HB, Kasiske BL, Schnitzler MA, Axelrod DA. Immunosuppression Regimen Use and Outcomes in Older and Younger Adult Kidney Transplant Recipients: A National Registry Analysis. Transplantation 2021; 105:1840-1849. [PMID: 33214534 PMCID: PMC10576532 DOI: 10.1097/tp.0000000000003547] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Although the population of older transplant recipients has increased dramatically, there are limited data describing the impact of immunosuppression regimen choice on outcomes in this recipient group. METHODS National data for US Medicare-insured adult kidney recipients (N = 67 362; 2005-2016) were examined to determine early immunosuppression regimen and associations with acute rejection, death-censored graft failure, and mortality using multivariable regression analysis in younger (18-64 y) and older (>65 y) adults. RESULTS The use of antithymocyte globulin (TMG) or alemtuzumab (ALEM) induction with triple maintenance immunosuppression (reference) was less common in older compared with younger (36.9% versus 47.0%) recipients, as was TMG/ALEM + steroid avoidance (19.2% versus 20.1%) and mammalian target of rapamycin inhibitor (mTORi)-based (6.7% versus 7.7%) treatments. Conversely, older patients were more likely to receive interleukin (IL)-2-receptor antibody (IL2rAb) + triple maintenance (21.1% versus 14.7%), IL2rAb + steroid avoidance (4.1% versus 1.8%), and cyclosporine-based (8.3% versus 6.6%) immunosuppression. Compared with older recipients treated with TMG/ALEM + triple maintenance (reference regimen), those managed with TMG/ALEM + steroid avoidance (adjusted odds ratio [aOR], 0.440.520.61) and IL2rAb + steroid avoidance (aOR, 0.390.550.79) had lower risk of acute rejection. Older patients experienced more death-censored graft failure when managed with Tac + antimetabolite avoidance (adjusted hazard [aHR], 1.411.782.25), mTORi-based (aHR, 1.702.142.71), and cyclosporine-based (aHR, 1.411.782.25) regimens, versus the reference regimen. mTORi-based and cyclosporine-based regimens were associated with increased mortality in both older and younger patients. CONCLUSIONS Lower-intensity immunosuppression regimens (eg, steroid-sparing) appear beneficial for older kidney transplant recipients, while mTORi and cyclosporine-based maintenance immunosuppression are associated with higher risk of adverse outcomes.
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Affiliation(s)
| | | | | | | | | | | | - Sunjae Bae
- Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - JiYoon B. Ahn
- Johns Hopkins School of Medicine, Baltimore, MD, USA
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Chayanupatkul M, Gambarin-Gelwan M, Schiano TD. The presence of non-hepatic malignancy and its implication in pursuing liver transplantation. Clin Transplant 2021; 35:e14410. [PMID: 34189778 DOI: 10.1111/ctr.14410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/13/2021] [Accepted: 06/27/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Primary extrahepatic malignancy and chronic liver disease co-exist in a considerable number of patients, creating a dilemma both in the aspects of liver transplant candidacy and cancer therapy. In this review, we will explore several aspects and controversies of liver transplantation in patients with non-hepatocellular carcinoma malignancy including risks of cancer recurrence after liver transplantation and the ethical dilemma of the selection of liver transplantation candidates with non-hepatic malignancy. METHODS We performed a search in several online databases and reviewed published articles and ongoing clinical trials in the topics of transplantation and pre-existing malignancies. RESULTS AND DISCUSSION Liver transplantation can be safely performed in selected patients with pre-existing extrahepatic malignancies with low recurrence rate if they have an expected 5-year survival rate of at least 50%. The cancer-free period before transplantation depends on the type, stage, and location of cancer. A shorter or no wait-time may be considered in an early stage cancer or carcinoma in situ. The urgency and benefits of liver transplantation should also be taken into consideration when determining a reasonable wait-time. This is particularly important in patients with decompensated cirrhosis who cannot afford to wait a few years before they can undergo liver transplantation.
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Affiliation(s)
- Maneerat Chayanupatkul
- Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Maya Gambarin-Gelwan
- Gastroenterology, Hepatology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Thomas D Schiano
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Recanati-Miller Transplantation Institute, New York, New York, USA
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Duran-Ortiz S, List EO, Basu R, Kopchick JJ. Extending lifespan by modulating the growth hormone/insulin-like growth factor-1 axis: coming of age. Pituitary 2021; 24:438-456. [PMID: 33459974 PMCID: PMC8122064 DOI: 10.1007/s11102-020-01117-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 02/06/2023]
Abstract
Progress made in the years of aging research have allowed the opportunity to explore potential interventions to slow aging and extend healthy lifespan. Studies performed in yeast, worms, flies and mice subjected to genetic and pharmacological interventions have given insight into the cellular and molecular mechanisms associated with longevity. Furthermore, it is now possible to effectively modulate pathways that slow aging at different stages of life (early life or at an adult age). Interestingly, interventions that extend longevity in adult mice have had sex-specific success, suggesting a potential link between particular pathways that modulate aging and sex. For example, reduction of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis at an adult age extends lifespan preferentially in females. Moreover, several postnatal dietary interventions tested by the 'Intervention Testing Program (ITP)' from the National Institute of Aging (NIA) have shown that while pharmacological interventions like rapamycin affect the IGF-1/insulin pathway and preferentially extend lifespan in females; dietary compounds that target other cellular pathways are effective only in male mice-indicating mutually exclusive sex-specific pathways. Therefore, a combination of interventions that target non-overlapping aging-related pathways appears to be an effective approach to further extend healthy lifespan in both sexes. Here, we review the germline and postnatal mouse lines that target the GH/IGF-1 axis as a mechanism to extend longevity as well as the dietary compounds that tested positive in the NIA program to increase lifespan. We believe that the interventions reviewed in this paper could constitute feasible combinations for an extended healthy lifespan in both male and female mice.
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Affiliation(s)
- Silvana Duran-Ortiz
- Edison Biotechnology Institute, Ohio University, Athens, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, USA
| | - Edward O List
- Edison Biotechnology Institute, Ohio University, Athens, USA
| | - Reetobrata Basu
- Edison Biotechnology Institute, Ohio University, Athens, USA
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, USA.
- Molecular and Cellular Biology Program, Ohio University, Athens, USA.
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA.
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Buxeda A, Redondo-Pachón D, Pérez-Sáez MJ, Crespo M, Pascual J. Sex differences in cancer risk and outcomes after kidney transplantation. Transplant Rev (Orlando) 2021; 35:100625. [PMID: 34020178 DOI: 10.1016/j.trre.2021.100625] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Kidney transplant recipients (KTRs) experience a two- to four-fold increased risk of developing and dying from cancer compared with the general population. High cancer risk results from the interaction of both modifiable and non-modifiable factors. This mapping review explores the impact of sex disparity on cancer's increased incidence and mortality after kidney transplantation (KT). In terms of age, population-based studies indicate that younger recipients of both sexes experience a higher risk of cancer, but this is more pronounced in young women. On the contrary, older men are more likely to be diagnosed with cancer, although their increased risk is not statistically significant compared with the general population. Regarding cancer type, studies show an increased risk of Kaposi sarcoma, gynecologic and lung cancer in women, and bladder and kidney cancer in men. Immune-related cancers such as pos-transplant lymphoproliferative disorders and melanoma are increased in both sexes. Mortality also shows differences between sexes. Although cancer is the second cause of death in both male and female KTRs, studies show higher overall mortality in men and elderly recipients. However, the relative risk of cancer mortality compared with the general population is higher at a younger age, with disparate results regarding sex. Female KTRs appear to die at a younger age than males when compared with the general population. Differences in cancer rates by sex after renal transplantation need further studies. A better understanding of sex-specific differences in cancer epidemiology after KT could help nephrologists to better address pre-transplant counseling, to establish early surveillance programs, and to plan modifiable risk factors such as immunosuppression.
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Affiliation(s)
- Anna Buxeda
- Department of Nephrology, Hospital del Mar, Barcelona, Spain.
| | | | | | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
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Association of HLA mismatch and MTOR inhibitor regimens with malignancy and mortality after kidney transplantation. Transpl Immunol 2021; 66:101391. [PMID: 33838299 DOI: 10.1016/j.trim.2021.101391] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/28/2021] [Accepted: 04/04/2021] [Indexed: 01/20/2023]
Abstract
Background The association of mammalian target of rapamycin inhibitors (MTORI) with malignancies and mortality in kidney transplant recipients (KTR) with different degrees of human leukocyte antigen mismatch (HLA-mm) at transplant has not been previously studied. Methods Our observational cohort study included 166, 256 adult KTRs in 2000-2018. Immunosuppression in the first post-transplant year were MTORIs in 13,056 (7.85%) and non-MTORIs in 153,200 (92.15%). We used Cox multivariable regression models to determine the cause-specific hazard ratio (HRcs) of non-melanoma skin cancer (NMSC),solid organ malignancies (SOM)] and all-cause death (deathac); and the HR of the composite outcomes of NMSC or deathac and SOM or deathac associated with MTORI versus non-MTORI regimens in the overall study sample and the 0, 1-3, and 4-6 HLA-A, B and DR mm subgroups. Results NMSC risk was lower with MTORI than non-MTORI in all HLA-mm subgroups [(0 mm, HRcs = 0.67; 95% CI = 0.46-0.97, 1-3 mm, HRcs = 0.73; 95% CI = 0.61-0.87, 4-6 mm, HRcs = 0.69; 95% CI = 0.62-0.76)]. SOM risks were similar between regimens in the 0 HLA mm subgroup (HRcs = 1.10 (95% CI = 0.78-1.57) and lower with MTORI than non-MTORI in the 1-3, and 4-6 HLA-mm subgroups, [(HR = 0.84; (95% CI = 0.71-0.99), and (HR = 0.86; 95% CI = 0.78-0.94); respectively]. Risks of deathac and composite outcomes (NMSC or deathac and SOM or deathac) were higher with MTORI than non-MTORI in almost all HLA-mm subgroups. Conclusion MTORIs are associated with protection from NMSC and SOM in almost all HLA-mm subgroups ca; however, their association with increased all-cause mortality in adult kidney transplant recipients needs further investigation.
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Anthony C, Imran M, Pouliopoulos J, Emmanuel S, Iliff JW, Moffat KJ, Ross J, Graham RM, Kotlyar E, Muthiah K, Keogh AM, Hayward CS, Macdonald P, Jabbour A. Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study). JACC-HEART FAILURE 2021; 9:301-313. [PMID: 33795116 DOI: 10.1016/j.jchf.2021.01.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 01/04/2021] [Accepted: 01/24/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVES This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 μg/l vs. 8.6 ± 2.8 μg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 μg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 μmol/l vs. 9 ± 21.8 μmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.
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Affiliation(s)
- Chris Anthony
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia
| | - Muhammad Imran
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia
| | - Jim Pouliopoulos
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia; Victor Chang Cardiac Research Institute
| | - Sam Emmanuel
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia
| | - James W Iliff
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia
| | - Kirsten J Moffat
- Medical Imaging Department, St. Vincent's Hospital, Sydney, Australia
| | - Joanne Ross
- Medical Imaging Department, St. Vincent's Hospital, Sydney, Australia
| | - Robert M Graham
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia; Victor Chang Cardiac Research Institute; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Eugene Kotlyar
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Kavitha Muthiah
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Anne M Keogh
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Christopher S Hayward
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia; Victor Chang Cardiac Research Institute; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Peter Macdonald
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia; Victor Chang Cardiac Research Institute; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Andrew Jabbour
- Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia; Victor Chang Cardiac Research Institute; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
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Growth and Viability of Cutaneous Squamous Cell Carcinoma Cell Lines Display Different Sensitivities to Isoform-Specific Phosphoinositide 3-Kinase Inhibitors. Int J Mol Sci 2021; 22:ijms22073567. [PMID: 33808215 PMCID: PMC8036316 DOI: 10.3390/ijms22073567] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 03/19/2021] [Indexed: 12/20/2022] Open
Abstract
Cutaneous squamous cell carcinomas (cSCCs) account for about 20% of keratinocyte carcinomas, the most common cancer in the UK. Therapeutic options for cSCC patients who develop metastasis are limited and a better understanding of the biochemical pathways involved in cSCC development/progression is crucial to identify novel therapeutic targets. Evidence indicates that the phosphoinositide 3-kinases (PI3Ks)/Akt pathway plays an important role, in particular in advanced cSCC. Questions remain of whether all four PI3K isoforms able to activate Akt are involved and whether selective inhibition of specific isoform(s) might represent a more targeted strategy. Here we determined the sensitivity of four patient-derived cSCC cell lines to isoform-specific PI3K inhibitors to start investigating their potential therapeutic value in cSCC. Parallel experiments were performed in immortalized keratinocyte cell lines. We observed that pan PI3Ks inhibition reduced the growth/viability of all tested cell lines, confirming the crucial role of this pathway. Selective inhibition of the PI3K isoform p110α reduced growth/viability of keratinocytes and of two cSCC cell lines while affecting the other two only slightly. Importantly, p110α inhibition reduced Akt phosphorylation in all cSCC cell lines. These data indicate that growth and viability of the investigated cSCC cells display differential sensitivity to isoform-specific PI3K inhibitors.
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Post-transplant lymphoproliferative disorder in adult renal transplant recipients: case series and review of literature. Cent Eur J Immunol 2021; 45:498-506. [PMID: 33658896 PMCID: PMC7882407 DOI: 10.5114/ceji.2020.103427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 10/28/2019] [Indexed: 01/24/2023] Open
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is serious life-threating complication of transplantation. The clinical picture differs from lymphomas observed in the general population, with different manifestation, histopathology, higher aggressiveness with involvement of sites beyond the primary lymph node, and poorer outcome. The objective of the study was to present nine cases of PTLD observed in our centre among the kidney transplant recipient population and discuss the results with up-to-date literature. We performed a retrospective single-centre assessment of PTLD incidence in the cohorts of kidney transplant recipients followed by our centre. We found nine cases of PTLD, five men and four woman, aged from 26 to 67 years at the time of diagnosis (mean [SD] 48 [5] years), transplanted between 1997 and 2013. The disease was diagnosed between 2002 and 2017, from 6 to 440 months after transplantation (mean [SD] 96 [137] months). A diffuse large B-cell lymphoma was found in seven cases early as well as late after transplantation, and two patients presented T-cell lymphoma. Five patients achieved complete remission with no relapses after 6 to 13 months of treatment. In three cases the remission was achieved by switching to mammalian target of rapamycin inhibitors (mTORi) only. Four recipients died from 2 weeks to 15 months after PTLD was diagnosed. Although the diagnostic criteria of different forms of PTLD are commonly known, rapid and correct diagnosis is not easy. PTLD is a relatively a rare disease, so there are too few studies and little consensus on the optimal treatment.
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Préterre J, Visentin J, Saint Cricq M, Kaminski H, Del Bello A, Prezelin-Reydit M, Merville P, Kamar N, Couzi L. Comparison of two strategies based on mammalian target of rapamycin inhibitors in secondary prevention of non-melanoma skin cancer after kidney transplantation, a pilot study. Clin Transplant 2021; 35:e14207. [PMID: 33369772 DOI: 10.1111/ctr.14207] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 12/10/2020] [Accepted: 12/16/2020] [Indexed: 01/05/2023]
Abstract
After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p = .37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p = .09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen.
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Affiliation(s)
- Julie Préterre
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France
| | - Jonathan Visentin
- CHU de Bordeaux, Service d'Immunologie et Immunogénétique, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Morgane Saint Cricq
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France
| | - Hannah Kaminski
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Arnaud Del Bello
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France.,Centre de Physiopathologie Toulouse Purpan, University Paul Sabatier, INSERM U1043, Toulouse, France
| | - Mathilde Prezelin-Reydit
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France
| | - Pierre Merville
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France.,Centre de Physiopathologie Toulouse Purpan, University Paul Sabatier, INSERM U1043, Toulouse, France
| | - Lionel Couzi
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
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Recurrent squamous cell carcinoma in a post cardiac transplant patient. Int J Surg Case Rep 2021; 79:275-280. [PMID: 33757259 PMCID: PMC7889445 DOI: 10.1016/j.ijscr.2021.01.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/03/2021] [Accepted: 01/09/2021] [Indexed: 11/23/2022] Open
Abstract
Patient having recurrent carcinomas following heart transplant due to possible immunosuppression. Early Cancer surveillance in transplant patients is necessary to detect and treat malignancies early. Unique in having two recurrences post-transplant. Introduction and importance Solid organ transplantation has evolved along with dramatic advancements in definitive treatment for irreversible and uncompensated organ failure. Transplanted organ survival has improved as a result of reduced allograft rejection. However, negative long-term outcomes which were largely due to the adverse effects of rapidly evolving immunosuppressive regimens are still evident. The emergence of malignancies following prolonged exposure to immunosuppression treatment has affected the quality of life in transplant recipients. They are approximately one hundred times more likely to develop squamous cell carcinoma (SCC) compared to the general population and the incidence of malignant melanomas, basal cell carcinomas, and Kaposi’s sarcomas are also on the rise. The incidence of de novo malignancies ranges from 9 to 21% and is commonly seen in the skin and the lymphoreticular system in these patients. Case presentation A 78-year-old male presented with a lump in the right axilla, which had grown in size over a 4-week period. Patient had received a cardiac transplant 9 years prior and was on a regimen of Tacrolimus and Mycophenolate Mofetil since then. Clinical discussion Following 4 years of immunosuppression therapy, the patient developed a non-healing ulcer on his right forearm and the biopsy confirmed SCC. The recent biopsy performed on the new axillary lump also confirmed SCC. Iatrogenic immune suppressive treatment is associated with the occurrence of de novo, non-melanoma skin cancers in the solid organ transplant recipients and this necessitates early and comprehensive cancer surveillance models to be included in the pre and post-transplant assessment. Conclusion Advances in immunology suggest that peripheral blood mononuclear cell sequencing and immune profiling to identify immune phenotypes associated with keratinocyte cancers allow us to recognize patients who are more susceptible for SCC following organ transplantation and immunosuppression.
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Ume AC, Pugh JM, Kemp MG, Williams CR. Calcineurin inhibitor (CNI)-associated skin cancers: New insights on exploring mechanisms by which CNIs downregulate DNA repair machinery. PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE 2020; 36:433-440. [PMID: 32786098 PMCID: PMC11042075 DOI: 10.1111/phpp.12600] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/22/2020] [Accepted: 08/02/2020] [Indexed: 12/31/2022]
Abstract
The use of the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus remains a cornerstone in post-transplantation immunosuppression. Although these immunosuppressive agents have revolutionized the field of transplantation medicine, its increased skin cancer risk poses a major concern. A key contributor to this phenomenon is a reduced capacity to repair DNA damage caused by exposure to ultraviolet (UV) wavelengths of sunlight. CNIs decrease DNA repair by mechanisms that remain to be fully explored. Though CsA is known to decrease the abundance of key DNA repair enzymes, less is known about how tacrolimus yields this effect. CNIs hold the capacity to inhibit both of the main catalytic calcineurin isoforms (CnAα and CnAβ). However, it is unknown which isoform regulates UV-induced DNA repair, which is the focus of this review. It is with hope that this insight spurs investigative efforts that conclusively addresses these gaps in knowledge. Additionally, this research also raises the possibility that newer CNIs can be developed that effectively blunt the immune response while mitigating the incidence of skin cancers with immunosuppression.
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Affiliation(s)
- Adaku C. Ume
- Department of Neuroscience, Cell Biology & Physiology, College of Science and Mathematics, Wright State University Boonshoft School of Medicine, Dayton, Ohio
| | - Jennifer M. Pugh
- Department of Neuroscience, Cell Biology & Physiology, College of Science and Mathematics, Wright State University Boonshoft School of Medicine, Dayton, Ohio
| | - Michael G. Kemp
- Department of Pharmacology & Toxicology, Wright State University Boonshoft School of Medicine, Dayton, Ohio
| | - Clintoria R. Williams
- Department of Neuroscience, Cell Biology & Physiology, College of Science and Mathematics, Wright State University Boonshoft School of Medicine, Dayton, Ohio
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Immunosuppressive regimens for adult liver transplant recipients in real-life practice: consensus recommendations from an Italian Working Group. Hepatol Int 2020; 14:930-943. [PMID: 33099753 PMCID: PMC7803715 DOI: 10.1007/s12072-020-10091-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 09/06/2020] [Indexed: 02/07/2023]
Abstract
It is a well-recognized fact that implementing new guidelines in clinical practice may be difficult; therefore the Italian Society for Organ and Tissue Transplantation (SITO) set out to define practical immunosuppression tools for the management of liver transplantation patients. In 2017, an Italian Working Group of liver transplant experts and hepatologists issued a set of consensus statements along with evidence-based recommendations on the use of everolimus after liver transplantation. This article presents the evidence- and consensus-based algorithms developed within the Italian Working Group, which are aimed towards guiding clinicians in the selection of immunosuppressive regimens for the management of adult liver transplant recipients in real-life practice. The liver transplant recipient population, typically managed in clinical practice, was divided into the following categories: (1) standard patients; (2) critically ill patients; (3) patients with a specific etiology; (4) patients with hepatocellular carcinoma; (5) and patients with de novo malignancies. The algorithms are divided into two parts, according to the time from transplantation (0-3 months and > 3 months) and are discussed here along with relevant supporting literature, when available. Ultimately, it is hoped that the evidence- and consensus-based algorithms developed within the Italian Working Group, and presented here, contribute to simplify, personalize, and optimize immunosuppression of liver transplantation recipients in clinical practice.
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Franzin R, Netti GS, Spadaccino F, Porta C, Gesualdo L, Stallone G, Castellano G, Ranieri E. The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand? Front Immunol 2020; 11:574271. [PMID: 33162990 PMCID: PMC7580288 DOI: 10.3389/fimmu.2020.574271] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are a novel class of immunotherapy drugs that have improved the treatment of a broad spectrum of cancers as metastatic melanoma, non-small lung cancer or renal cell carcinoma. These humanized monoclonal antibodies target inhibitory receptors (e.g. CTLA-4, PD-1, LAG-3, TIM-3) and ligands (PD-L1) expressed on T lymphocytes, antigen presenting cells and tumor cells and elicit an anti-tumor response by stimulating immune system. Nevertheless, the improved overall survival is complicated by the manifestation of Immune-related Adverse Effects (irAEs). During treatment with ICIs, the most common adverse kidney effect is represented by the development of acute kidney injury (AKI) with the acute tubulointerstitial nephritis as recurrent histological feature. The mechanisms involved in ICIs-induced AKI include the re-activation of effector T cells previously stimulated by nephrotoxic drugs (i.e. by antibiotics), the loss of tolerance versus self-renal antigens, the increased PD-L1 expression by tubular cells or the establishment of a pro-inflammatory milieu with the release of self-reactive antibodies. For renal transplant recipient treated with ICIs, the increased incidence of rejection is a serious concern. Therefore, the combination of ICIs with mTOR inhibitors represents an emerging strategy. Finally, it is relevant to anticipate which patients under ICIs would experience severe irAEs and from a kidney perspective, to predict patients with higher risk of AKI. Here, we provide a detailed overview of ICIs-related nephrotoxicity and the recently described multicenter studies. Several factors have been reported as biomarkers of ICIs-irAEs, in this review we speculate on potential biomarkers for ICIs-associated AKI.
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Affiliation(s)
- Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giuseppe Stefano Netti
- Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Federica Spadaccino
- Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Camillo Porta
- Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Elena Ranieri
- Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Long-term Follow-up From the Randomized SCHEDULE Study. Transplantation 2020; 104:154-164. [PMID: 30893292 DOI: 10.1097/tp.0000000000002702] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND A calcineurin inhibitor (CNI)-free immunosuppressive regimen has been demonstrated to improve renal function early after heart transplantation, but long-term outcome of such a strategy has not been well described. METHODS In the randomized SCHEDULE trial, de novo heart transplant recipients received (1) everolimus with reduced-exposure CNI (cyclosporine) followed by CNI withdrawal at week 7-11 posttransplant or (2) standard-exposure cyclosporine, both with mycophenolate mofetil and corticosteroids; 95/115 randomized patients were followed up at 5-7 years posttransplant. RESULTS Mean measured glomerular filtration rate was 74.7 mL/min and 62.4 mL/min with everolimus and CNI, respectively. The mean difference was in favor of everolimus by 11.8 mL/min in the intent-to-treat population (P = 0.004) and 17.2 mL/min in the per protocol population (n = 75; P < 0.001). From transplantation to last follow-up, the incidence of biopsy-proven acute rejection (BPAR) was 77% (37/48) and 66% (31/47) (P = 0.23) with treated BPAR in 50% and 23% (P < 0.01) in the everolimus and CNI groups, respectively; no episode led to hemodynamic compromise. Coronary allograft vasculopathy (CAV) assessed by coronary intravascular ultrasound was present in 53% (19/36) and 74% (26/35) of everolimus- and CNI-treated patients, respectively (P = 0.037). Graft dimensions and function were similar between the groups. Late adverse events were comparable. CONCLUSIONS These results suggest that de novo heart transplant patients randomized to everolimus and low-dose CNI followed by CNI-free therapy maintain significantly better long-term renal function as well as significantly reduced CAV than patients randomized to standard CNI treatment. Increased BPAR in the everolimus group during year 1 did not impair long-term graft function.
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Abstract
Cancer is an important cause of morbidity and mortality after liver transplantation and can occur through three mechanisms: recurrence of a recipient's pre-transplant malignancy, donor-related transmission and de novo development. Currently, the decision to list a patient with a history of malignancy is an individual one. Screening guidelines for potential donors and for recipients after transplant are still widely based on general population guidelines, while the role of chronic immunosuppression remains controversial. These shortcomings mean that patients present at diagnosis with advanced stages of the disease, often precluding curative treatments. The present review summarizes current recommendations for the screening of recipients and donors for pre- and post-transplant malignancies, and current management of recipients who develop cancer after a liver transplant.
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Ueno T, Kodama T, Noguchi Y, Deguchi K, Nomura M, Saka R, Watanabe M, Tazuke Y, Bessho K, Okuyama H. Safety and Efficacy of Everolimus Rescue Treatment After Pediatric Living Donor Liver Transplantation. Transplant Proc 2020; 52:1829-1832. [PMID: 32571711 DOI: 10.1016/j.transproceed.2020.01.159] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/26/2020] [Indexed: 01/01/2023]
Abstract
PURPOSE Everolimus (EVR) is a derivative of sirolimus with a similar mechanism of action. The safety and efficacy of EVR after pediatric living donor liver transplantation (LDLT) are currently unknown. The purpose of this study was to examine the safety and efficacy of EVR as rescue therapy after pediatric LDLT. METHODS This study included patients younger than 19 years of age who received EVR after LDLT at our institution. EVR was administered as rescue treatment in addition to tacrolimus. In 21 patients, EVR dose, trough level, outcomes, and adverse effects were assessed. RESULTS Original diseases of patients consisted of biliary atresia (n = 11), Alagille syndrome (n = 3), fulminant hepatitis (n = 3), hepatoblastoma (n = 2), and other (n = 2). Mean age at transplant was 2.0 years (range 0.6-6.2 years). Mean age at initial EVR administration was 8.0 years (range 0.9-18.9 years). Indications for EVR use were graft fibrosis (n = 8), refractory acute cellular rejection (n = 5), renal sparing (n = 4), hepatoblastoma (n = 2), and chronic rejection (CR) (n = 2). Mean duration of administration was 17.1 months (range 2.1-60.4 months). Mean dose was 0.5 mg/m2 twice daily. Mean EVR trough level was 2.5 ng/mL (range 1.5-5.0 ng/mL). Liver function improved and fibrosis did not progress in all patients with CR. However, 14 patients (67%) experienced adverse effects that required EVR dose reduction or discontinuation. CONCLUSION EVR is tolerable for pediatric patients after LDLT with dose adjustment. EVR had a certain effect to relieve progression on CR. Further follow-up is required.
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Affiliation(s)
- Takehisa Ueno
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
| | - Tasuku Kodama
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuki Noguchi
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Koichi Deguchi
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Motonari Nomura
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryuta Saka
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Miho Watanabe
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuko Tazuke
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kazuhiko Bessho
- Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hiroomi Okuyama
- Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Abstract
T-cell immunity undergoes a complex and continuous remodeling with aging. Understanding those dynamics is essential in refining immunosuppression. Aging is linked to phenotypic and metabolic changes in T-cell immunity, many resulting into impaired function and compromised effectiveness. Those changes may impact clinical immunosuppression with evidences suggesting age-specific efficacies of some (CNI and mammalian target of rapamycin inhibitors) but not necessarily all immunosuppressants. Metabolic changes of T cells with aging have only recently been appreciated and may provide novel ways of immunosuppression. Here, we provide an update on changes of T-cell immunity in aging.
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